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Phenotypic and genotypic characterisation of Pseudomonas aeruginosa isolates from people with bronchiectasis Ross Phoenix McCleave (24168210) PUREID: 529262506 Pseudomonas aeruginosa Bronchiectasis Inhaled antibiotics Bronchiectasis is a chronic lung condition characterised by irreversible dilation of the lower respiratory tract airways. Infection with Pseudomonas aeruginosa is common in people with bronchiectasis and is associated with increased rates of hospitalisation, morbidity, and mortality. Recently, a clinical trial (iBEST-1 study, NCT02712983) found that tobramycin inhalation powder (TIP) was safe and effective to treat chronic P. aeruginosa infection within this cohort and the emergence of tobramycin resistance only occurred occasionally. <br><br>The main aim of this thesis was to characterise and compare P. aeruginosa strain infection, antimicrobial resistance and tolerance, virulence traits and fitness prior to and following exposure to tobramycin. Prospectively collected clinical isolates from the iBEST-1 study, as well as isolates which had tobramycin resistance evolved in vitro, were included. <br>The clinical P. aeruginosa isolate genotypes were diverse and there was little or no evidence of infection with strains, including previously characterised shared strains, found in people with cystic fibrosis. Most iBEST-1 participants were infected with a single strain throughout the trial, and infection with multiple strains did not affect treatment outcomes. Furthermore, there was a modest increase in the tobramycin minimum inhibitory concentration (MIC) following treatment with TIP in isogenic pairs of clinical P. aeruginosa isolates, however most isolates remained clinically susceptible to tobramycin. In a selection of tobramycin susceptible isogenic isolates, planktonic tolerance and persistence increased following TIP treatment but not placebo, and most isolates were able to survive in concentrations far exceeding their MIC when growing in biofilms. Finally, the experimental evolution of tobramycin resistance in clinical isolates was clearly associated with reduced flagellar motility and growth rates, and increased lag times. In lineages with experimentally evolved resistance, mutations in the fusA1 gene were commonly acquired and were associated with the development of a stable resistant phenotype. <br><br>This thesis shows that treatment with TIP was not associated with the acquisition of new P. aeruginosa strains. Although treatment with TIP did not drive the emergence of tobramycin resistance, there was an increase in bacterial tolerance which may be a clinical concern. Similarly, biofilm growth may help explain why P. aeruginosa infection was sustained in some patients. In clinical isolates which do develop resistance, tobramycin pressure may also contribute to phenotypic shifts in P. aeruginosa that are commonly observed over time in chronic lung infections and mutations in fusA1 might be an important resistance mechanism. 2026-10-01T16:45:11Z Text Thesis 10.17034/32638806.v1 https://figshare.com/articles/thesis/Phenotypic_and_genotypic_characterisation_of_Pseudomonas_aeruginosa_isolates_from_people_with_bronchiectasis/32638806 All Rights Reserved